Lung cancer is so closely associated with smoking that people who have never smoked may assume their risk is extremely low. But new research has identified a rare inherited genetic mutation that appears capable of changing that risk dramatically.
Researchers studying genetic data from more than 3 million people identified an inherited mutation called EGFR T790M. Among people who had never smoked, carriers had roughly 62 times the lung-cancer risk of people who did not carry the mutation.
The mutation is extremely rare, so this finding does not mean nonsmokers generally face that level of risk. What makes the discovery striking is the size of the effect tied to a single inherited genetic change.
Researchers looked at genetic data from more than 3 million people
Because EGFR T790M is so uncommon, earlier research struggled to determine exactly how much lung-cancer risk it carries. A much larger dataset finally gave researchers enough carriers to examine the connection more closely.
In the study published in Science, researchers analyzed genetic data from approximately 3.37 million people of European ancestry.
They focused on germline EGFR T790M, meaning the mutation is present in the inherited DNA a person is born with rather than appearing only later inside a tumor.
Across the full group, carrying the mutation was associated with about 25 times the risk of lung cancer compared with not carrying it.
But the association became much stronger when researchers looked specifically at people who had never smoked. Among never-smokers, carriers had roughly 62 times the lung-cancer risk of non-carriers.
Takeaway: A rare inherited mutation was associated with an unusually large increase in lung-cancer risk, particularly among people who had never smoked.
The finding challenges a familiar assumption about lung cancer
Smoking remains one of the most important risk factors for lung cancer, but it is not the only way the disease develops. Genetics can also play a role, and this mutation offers an unusually clear example.
Researchers found that smoking was associated with roughly four times the risk of lung cancer in the population they studied.
That does not make smoking less dangerous. It shows just how strong the association with EGFR T790M was among carriers, especially those who had never smoked.
The distinction is important because people sometimes interpret a nonsmoking history as meaning lung cancer is almost impossible.
In reality, lung cancer can also be influenced by factors such as secondhand smoke, radon, occupational exposures, air pollution and inherited genetic susceptibility.
This study helps researchers understand one rare genetic pathway that may explain why the disease develops in some people who have never used tobacco.
Takeaway: Never smoking greatly removes one major risk factor, but it does not eliminate every pathway through which lung cancer can develop.
This mutation appears unusually specific to the lungs
Researchers also wanted to know whether carrying EGFR T790M increased the risk of many diseases or showed a more specific relationship with lung cancer.
The mutation was not significantly associated with the other common cancers and respiratory conditions examined in the study.
Save this article
Enter your email address and we'll send it straight to your inbox.
That suggests its strongest effect may be concentrated in lung cancer rather than representing a general inherited tendency toward many different cancers.
EGFR, or epidermal growth factor receptor, is a gene involved in controlling how cells grow and divide. Changes in this gene are already well known in certain lung cancers.
The inherited T790M mutation is different from many EGFR mutations discovered only after a tumor has developed because carriers can be born with it in cells throughout the body. Researchers are still working to understand why some carriers eventually develop cancer and others do not.
Related: 10 Dangerous Myths About Smoking We Were All Led to Believe (And What the Science Really Shows)
Takeaway: The mutation appears to have a particularly strong connection with lung cancer, raising new questions about why lung tissue is so vulnerable in carriers.
Researchers traced much of its American ancestry to Southern Appalachia
The genetics also revealed something unexpected about history. Many U.S. carriers appeared to share ancestry connected to populations in Southern Appalachia.
Researchers found disproportionately high concentrations of EGFR T790M carriers in parts of the region, particularly Tennessee and Alabama.
Their genetic analysis suggested that many carriers descended from a shared ancestral lineage associated with British and Irish settlers who arrived in the United States during the colonial era.
Over generations, the mutation appears to have become more concentrated in relatively isolated populations through what geneticists call a founder effect and population bottleneck.
The mutation remains rare nationally. Researchers estimated its prevalence in the U.S. population at roughly one in 15,000 people, though it may be considerably more common in certain southeastern communities.
That history shows how migration and ancestry can influence the distribution of disease-related genetic variants hundreds of years later.
Takeaway: A genetic change carried through generations may help explain why this rare lung-cancer risk factor is concentrated in particular U.S. populations.
The discovery could eventually change who gets screened
Current lung-cancer screening recommendations largely focus on people with significant smoking histories, which means many lifelong nonsmokers do not qualify for routine screening. A powerful inherited risk factor raises the possibility that genetics could eventually help identify another high-risk group.
That does not mean everyone should now be tested for EGFR T790M. The mutation is rare, and researchers still need to determine the best way to translate the discovery into screening or prevention strategies.
They also need to understand the absolute lifetime risk faced by carriers, how other genes and environmental exposures interact with the mutation, and why some carriers never develop cancer.
Future studies are expected to include more diverse populations because the large genetic dataset used in this analysis primarily involved people of European ancestry.
Still, the research points toward a broader shift in how cancer risk may eventually be assessed. Smoking history may remain crucial, but for a small number of people, inherited DNA could tell an equally important part of the story.
Question for you. Would knowing that lung cancer can sometimes have a strong inherited component change how you think about genetic testing and cancer screening?
